Aqueous polymer dispersions for stabilizing actives

ABSTRACT

An aqueous dispersion comprising: a) from 5 to 99.9% by weight, based on the weight of solids in the aqueous dispersion, of one or more polymers having a number average molecular weight less than 10,000; b) from 0.1 to 94.9% by weight, based on the weight of solids in the aqueous dispersion, of one or more active ingredients selected from the group consisting of water soluble active ingredients, partially water soluble active ingredients, water insoluble active ingredients and combinations thereof; and c) from 30% to 95% by weight of water.

This application claims the benefit of U.S. Patent Application No.60/741,323 filed on Dec. 1, 2005.

The present invention relates to aqueous polymer dispersions andpolymers useful for stabilizing one or more active ingredients. Inparticular, the invention is an aqueous polymer dispersion that hasutility in stabilizing one or more active ingredients. Moreparticularly, the invention is directed to aqueous polymer dispersionsthat stabilize water soluble active ingredients, partially water solubleactive ingredients and water insoluble active ingredients andcombinations thereof.

U.S. Pat. No. 5,142,010 discloses a polymer composition that preventsmicrobial growth through the presence of strong biocidal groupschemically bonded to functional groups of the polymer. It discloses anantimicrobial composition comprising a polymer, including copolymers,terpolymers, and oligomers having pendent-active functional groupsconsisting of common amine substituents. One problem with such polymersis that the microbicide product is intended to remain in the polymercomposition to prevent growth of microorganisms on a substrate. It isdesirable to provide low molecular weight polymer compositions thatstabilize one or more active ingredients that are water soluble,partially water soluble, water insoluble and combinations thereof.Combining the low molecular weight polymer stabilized activeingredient(s) with a chemically and/or structurally related highermolecular weight polymer then effects release of the one or more activeingredients from the polymer mixture.

Accordingly, the invention provides an aqueous dispersion comprising:(a) from 5 to 99.9% by weight, based on the weight of solids in theaqueous dispersion, of one or more polymers having a number averagemolecular weight less than 10,000; and (b) from 0.1 to 95% by weight,based on the weight of solids in the aqueous dispersion, of one or moreactive ingredients selected from the group consisting of water solubleactive ingredients, partially water soluble active ingredients, waterinsoluble active ingredients and combinations thereof.

The invention further provides an aqueous dispersion comprising: a) from5 to 99.9% by weight, based on the weight of solids in the aqueousdispersion, of one or more polymers having a number average molecularweight less than 10,000; b) from 0.1 to 94.9% by weight, based on theweight of solids in the aqueous dispersion, of one or more activeingredients selected from the group consisting of water soluble activeingredients, partially water soluble active ingredients, water insolubleactive ingredients and combinations thereof; and c) from 30% to 95% byweight of water.

The invention provides an aqueous dispersion comprising: (a) from 5 to49.9% by weight, based on the weight of solids in the aqueousdispersion, of one or more polymers having a number average molecularweight less than 10,000; (b) from 0.1 to 45% by weight, based on theweight of solids in the aqueous dispersion, of one or more activeingredients selected from the group consisting of water soluble activeingredients, partially water soluble active ingredients, water insolubleactive ingredients and combinations thereof; and (c) from 94.9 to 5.1%by weight, based on the weight of solids in the aqueous dispersion, ofone or more film forming polymers having a number average moleculargreater than 10,000; wherein the one or more active ingredients arepartitioned in (a) prior to combining the components and water.

The invention provides a composition comprising: (a) from 5 to 49.9% byweight, based on the weight of the composition, of one or more polymershaving a number average molecular weight less than 10,000; (b) from 0.1to 45% by weight, based on the weight of the composition, of one or moreactive ingredients selected from the group consisting of water solubleactive ingredients, partially water soluble active ingredients, waterinsoluble active ingredients and combinations thereof; and (c) from 94.9to 5.1% by weight, based on the weight of the composition, of one ormore film forming polymers having a number average molecular greaterthan 10,000; wherein the one or more active ingredients are partitionedin (a) prior to combining the components.

The invention also provides a film prepared from the aqueous dispersionand a film prepared from the composition. The invention also provides acoating prepared from the aqueous dispersion and a coating prepared fromthe composition. The invention also provides an adhesive prepared fromthe aqueous dispersion and an adhesive prepared from the composition.The invention also provides a delivery system for releasing one or moreactive ingredients prepared from the aqueous dispersion or from thecomposition.

The invention also provides a method for stabilizing one or more activeingredients comprising the steps of: a) preparing an aqueous dispersioncomprising from 5 to 99.9% by weight, based on the weight of solids inthe aqueous dispersion, of one or more polymers having a number averagemolecular weight less than 10,000; and b) combining the aqueousdispersion with from 0.1 to 95% by weight, based on the weight of solidsin the aqueous dispersion, of one or more active ingredients selectedfrom the group consisting of water soluble active ingredients, partiallywater soluble active ingredients, water insoluble active ingredients andcombinations thereof.

The invention also provides a method for releasing one or more activeingredients from an aqueous dispersion comprising: a) preparing a firstaqueous dispersion comprising from 5 to 49.9% by weight, based on theweight of solids in the aqueous dispersion, of one or more polymershaving a number average molecular weight less than 10,000; b) combiningthe aqueous dispersion with from 0.1 to 45% by weight, based on theweight of solids in the aqueous dispersion, of one or more activeingredients selected from the group consisting of water soluble activeingredients, partially water soluble active ingredients, water insolubleactive ingredients and combinations thereof; and c) combining the firstaqueous dispersion with a second aqueous dispersion from 94.9 to 5.1% byweight, based on the weight of the composition, of one or more filmforming polymers having a number average molecular greater than 10,000;wherein the one or more active ingredients are partitioned in the firstaqueous dispersion prior to combining with the second aqueousdispersion; and d) drying the mixture of aqueous dispersions to form afilm or a coating.

The invention also provides a method for releasing one or more activeingredients stabilized with an aqueous dispersion comprising theadditional step of drying the blend of the aqueous dispersion.

The invention also provides a method for including large amounts of(also referred to as high loading) of active ingredients using the lowmolecular weight polymers of the invention as aqueous dispersions. Theinvention also provides a method for including small amounts of (lowloadings) of highly active ingredients using the low molecular weightpolymers of the invention as aqueous dispersions. The invention alsoprovides a method for releasing a constant concentration of one or moreAIs to an environment of use, including but not limited to mammalianskin.

The invention also provides a method for controlling the domain size ofthe active ingredient from 1000 microns to 1 nm, including AI domainsbelow 10 microns in size and including AI domains below 1 micron insize.

The invention also provides a method in controlling the morphology ofthe composite film with regard to the distribution and location of theactive ingredient such that the AI domains are homogeneously distributedin the polymer film matrix, or are concentrated at the surface of thefilm, or distributed as a gradient in the film.

The invention also provides a method for including a plurality ofdomains of different active ingredients using one or more polymershaving a low molecular weight.

The invention also provides a method of controlling the release rate andprofile of the active ingredients using polymers of the inventionthrough the control of particle size, domain size, domain distribution,and concentration.

As used herein, the term “dispersion” refers to a physical state ofmatter that includes at least two distinct phases, wherein a first phaseis distributed in a second phase, with the second phase being acontinuous medium including but not limited to water. An aqueous polymerdispersion is a dispersion containing a first phase distributed in anaqueous second phase that is predominately water. As used herein, theterm “stabilizing” refers to controlling or maintaining a polymerparticle size or the particle size of one or more active ingredientsincorporated in a polymer. The term “stabilizing” also refers topreventing crystallization or recrystallization of one or more activeingredients incorporated in a polymer. Alternatively, the term“stabilizing” as it pertains to one or more active ingredientsstabilized by an aqueous polymer dispersion refers to the one or moreactive ingredients exhibiting the following behavior including but notlimited to for example dissolving, encapsulating, partitioning, swellingand combinations thereof in the aqueous polymer dispersion. As usedherein, the terms water soluble, partially water soluble and waterinsoluble are defined as disclosed in U.S. Pat. No. 5,521,266. As usedherein active ingredients refers to any compound having biologicalactivity, including pharmaceutical activity, including compounds havinga chemical/physical response and including synthetic, semi-synthetic andnaturally occurring compounds.

Unless otherwise specified, the term particle size as used herein refersto the number average particle diameter as determined using a capillaryhydrodynamic fractionation apparatus, such as the Matec CHDF-2000apparatus (Matec Applied Sciences, MA) with ultraviolet detection at 200nm. Particle size standards are provided by National Institute ofStandards and Technology (NIST) traceable polystyrene standards of 50 to800 nm, such as supplied by Duke Scientific Corporation, CA. Particlesize was also determined by optical microscopy or using a BrookhavenInstruments Corp. 90Plus Particle Size Analyzer. Solids were determinedby weight loss after 40 minutes at 150° C. Molecular weight distributionwas determined by GPC analysis on a Polymer labs Mixed C 300×7.5 mmcolumn connected to an HP1100 auto-sampler and pump equipped with aPolymer Labs evaporative light scattering detector using polystyrenestandards. Films prepared from the aqueous dispersions werecharacterized by electron microscopy, including transmission electronmicroscopy (TEM) and scanning probe microscopy (SPM, AFM). Wheneverappropriate, particle size is measured by optical microscopy (LeitzOrthoplan with 100× oil immersion lens). Domain sizes are determined byTransmission Electron Microscopy with sample obtained from cryogenicmicrotoning of the film and RuO₄ staining. The domain size can also beinferred from the particle size of the aqueous dispersion of activeingredients in the low molecular polymer matrix.

Unless otherwise specified, the term Mn, as used herein, refers to thenumber average molecular weight as determined by size exclusionchromatography (SEC) using EasiCal PS-2® polystyrene standards suppliedby Polymer Laboratories.

Unless otherwise specified the term Mw, as used herein, refers to theweight average molecular weight as determined by SEC using EasiCal PS-2®polystyrene standards supplied by Polymer Laboratories.

The term Tg as used herein refers to the glass transition temperature ofpolymers as determined using the Fox equation (T. G. Fox, Bull. Am.Physics Soc., Volume 1, Issue No. 3, page 123(1956)). By “measured Tg,”as used herein, is meant the glass transition temperature as determinedby differential scanning calorimetry (DSC) using a heating rate of 10°C./minute, taking the mid-point in the heat flow versus temperaturetransition as the Tg value.

As used herein, the use of the term “(meth)” followed by another termsuch as acrylate refers to both acrylates and methacrylates. Forexample, the term “(meth)acrylate” refers to either acrylate ormethacrylate; the term “(meth)acrylic” refers to either acrylic ormethacrylic; the term “(meth)acrylic acid” refers to either acrylic acidor methacrylic acid; and the term “(meth)acrylamide” refers to eitheracrylamide or methacrylamide.

High molecular weight aqueous polymer dispersions useful in accordancewith the invention comprise polymer particles having a weight averagemolecular weight polymer greater than 10,000, including up to 100,000,also including up to 500,000 including up to 1,000,000 and includingless than 2,000,000. Suitable high molecular weight polymers include butare not limited to emulsion polymers.

Low molecular weight aqueous polymer dispersions (also referred to as“oligomers” or “oligomer dispersions”) comprise polymer particles havinga number average molecular weight polymer less than 10,000, includingless than 5,000 and including less than 3,000. The Mn of oligomerdispersions also is between 1,000 and 10,000. Suitable low molecularweight polymers include but are not limited to emulsion polymers. Themolecular weight of oligomer dispersions are controlled by any meansknown to the art.

According to one embodiment, the chain transfer agent is selected frommercaptans, polymercaptans, thioesters, halogenated compounds, organicsolvents including but not limited to alcohols, isopropanol, isobutanoland combinations thereof. In some preferred embodiments the molecularweight of oligomer dispersions is controlled through the use of linearor branched C₄-C₂₂ alkyl mercaptans such as n-dodecyl mercaptan andt-dodecyl mercaptan. It is also contemplated that the molecular weightof oligomer dispersions may be controlled through the use of catalyticchain transfer agents, such as the cobalt compounds described in U.S.Pat. Nos. 5,962,609 and 4,746,713. According to a separate embodiment,the molecular weight of the oligomer is controlled by isopropyl alcoholas the solvent a solution polymerization.

Low molecular weight polymer dispersions or oligomer dispersions areformed by any means known in the art including, for example, bulk,solution, emulsion, mini-emulsion, micro-emulsion, or suspensionpolymerization processes. Oligomers are also be formed by bulk orsolution polymerization. For solution polymerization, the chain transferagent may be the solvent such as isopropyl alcohol. The low molecularweight polymer is isolated by evaporation of the solvent. The lowmolecular weight polymer dispersions or “oligomer” dispersions may beprepared by emulsification of the low molecular weight polymer in water.According to one embodiment, the polymer having a Mn<10,000 or“oligomer” is formed by the free radical initiated polymerization of oneor more ethylenically unsaturated monomers. According to a separateembodiment, other forms of initiation, including anionic initiation, arecontemplated. In one such embodiment, the oligomer is formed by hightemperature oligomerization processes as disclosed in U.S. Pat. No.5,710,227. If oligomers are formed by means other than aqueousdispersion processes, they are converted to an aqueous dispersion bytechniques known to the art. According to a separate embodiment, theoligomer dispersion is prepared as an aqueous dispersion and water isremoved, creating an oligomer oil. When acrylic monomers are used toprepare the low molecular weight polymer and acrylic oil (AO) isprepared. According to a separate embodiment, the oligomer dispersion isprepared by solution polymerization which directly produces an oligomeroil. When acrylic monomers are used to prepare the low molecular weightpolymer and acrylic oil (AO) is prepared. The oligomer can bere-emulsified or converted to an aqueous dispersion by conventionaltechniques known in the art. According to a separate embodiment, theoligomer is prepared as polymer solids and emulsified to form an aqueousdispersion by conventional techniques known in the art.

Advantages of preparing the oligomer as an oil are that particle size iscontrolled and when combined with one or more active ingredients thatare partially soluble or water insoluble the domain size of the activeingredients is also controlled. The distribution and location of thedispersion in a polymer matrix such as a film is also controlled.

Another advantage of the invention is that low molecular weight polymersprovide a method for controlling and adjusting the loading of one ormore active ingredients in the aqueous dispersion. High amounts of oneor more actives (up to 95% by weight) to low amounts (<0.5% by weight)of one or more highly active ingredients can be loaded into the polymersor prepared as a polymer composition.

Another advantage of the invention is that low molecular weight polymersprovide a method for controlling the domain size of the activeingredient from 1000 microns to 1 nm, including AI domains below 10microns in size and including AI domains below 1 micron in size.

Another advantage of the invention is that low molecular weight polymersprovides a method for controlling morphology of a polymer film orcomposite film with regard to the distribution and location of theactive ingredient such that the AI domains are homogeneously distributedin the polymer film matrix, or are concentrated at the surface of thefilm, or distributed as a gradient in the film.

Another advantage of the invention is that low molecular weight polymersprovides a method for including a plurality of domains of differentactive ingredients using one or more polymers having a low molecularweight.

Another advantage of the invention is that low molecular weight polymersprovides a method of controlling the releasing rate and profile of theactive ingredients using polymers of the invention through the controlof particle size, domain size, domain distribution, and concentration.

The high molecular weight and low molecular weight polymers of theinvention include polymers formed by the polymerization of one or moreethylenically unsaturated monomers, condensation polymers, hybridpolymers containing both condensation polymer and addition polymer.Condensation polymers are polymers that are not formed by the additionpolymerization of ethylenically unsaturated monomers, and include, forexample, polyurethanes, polyureas, polyesters, polyamides, alkyds,polycarbonates, polysilicones such as the condensation product ofhexamethylcyclotrisiloxane (D₃); octamethylcyclotetrasiloxane (D₄), anddecamethylcyclopentasiloxane (D₅); polyalkyl oxides such as polyethyleneoxide; polyimides; polysulfones; polyacetals; and biopolymers such aspolyhydroxy alkanoates, polypeptides, and polysaccharides.

Both high molecular weight and low molecular weight polymers useful inaccordance with the invention are prepared by the polymerization of oneor more ethylenically unsaturated monomers and are polymerized by anymeans known in the art including solution, emulsion, mini-emulsion,microemulsion, or suspension polymerization processes. Preferred isemulsion or mini-emulsion. The practice of emulsion polymerization isdiscussed in detail in D. C. Blackley, Emulsion Polymerization (Wiley,1975) and H. Warson, The Applications of Synthetic Resin Emulsions,Chapter 2 (Ernest Benn Ltd., London 1972).

In those embodiments of the invention utilizing emulsion ormini-emulsion polymerization processes conventional surfactants may beused such as, for example, anionic and/or nonionic emulsifiers such as,for example, alkali metal or ammonium salts of alkyl, aryl, or alkylarylsulfates, sulfonates or phosphates; alkyl sulfonic acids; sulfosuccinatesalts; fatty acids; ethylenically unsaturated surfactant monomers; andethoxylated alcohols or phenols. The amount of surfactant used isusually 0.1% to 6% by weight, based on the weight of monomer. Eitherthermal or redox initiation processes may be used. The reactiontemperature is typically maintained at a temperature lower than 100° C.throughout the course of the reaction. Preferred is a reactiontemperature between 30° C. and 95° C., more preferably between 50° C.and 90° C. The monomer mixture may be added neat or as an emulsion inwater. The monomer mixture may be added in one or more additions orcontinuously, linearly or not, over the reaction period or combinationsthereof.

According to one embodiment, both high and low molecular weight polymersof the invention are formed by polymerization of ethylenicallyunsaturated monomers using conventional free radical initiators such as,for example, ammonium or sodium persulfate, hydrogen peroxide, sodiumperoxide, potassium peroxide, t-butyl hydroperoxide, cumenehydroperoxide, ammonium and/or alkali metal persulfates, sodiumperborate, perphosphoric acid and salts thereof, potassium permanganate,and ammonium or alkali metal salts of peroxydisulfuric acid, typicallyat a level of 0.01% to 3.0% by weight, based on the weight of totalmonomer. Redox systems using the same initiators (alternatively referredto as “oxidants” herein) coupled with a suitable reductant such as, forexample, sodium sulfoxylate formaldehyde, ascorbic acid, isoascorbicacid, alkali metal and ammonium salts of sulfur-containing acids, suchas sodium sulfite, bisulfite, thiosulfate, hydrosulfite, sulfide,hydrosulfide or dithionite, formadinesulfinic acid,hydroxymethanesulfonic acid, sodium 2-hydroxy-2-sulfinatoacetic acid,acetone bisulfite, amines such as ethanolamine, glycolic acid, glyoxylicacid hydrate, lactic acid, glyceric acid, malic acid, tartaric acid andsalts of the preceding acids may be used. Redox reaction catalyzingmetal salts of iron, copper, manganese, silver, platinum, vanadium,nickel, chromium, palladium, or cobalt may be used.

Ethylenically unsaturated nonionic monomers useful in preparing polymershaving Mn>10,000 and polymers having Mn<10,000 in accordance with theinvention include, for example, (meth)acrylic ester monomers includingmethyl acrylate, ethyl acrylate, butyl acrylate, 2-ethylhexyl acrylate,decyl acrylate, lauryl acrylate, methyl methacrylate, butylmethacrylate, isodecyl methacrylate, lauryl methacrylate, hydroxyethylmethacrylate, hydroxypropyl methacrylate, styrene, substituted styrenes,ethylene, butadiene; vinyl acetate, vinyl butyrate and other vinylesters; vinyl monomers such as vinyl chloride, vinyl toluene, and vinylbenzophenone; and vinylidene chloride.

Ethylenically unsaturated acid monomers useful in preparing polymershaving Mn>10,000 and polymers having Mn<10,000 in accordance with theinvention include, for example, acrylic acid, methacrylic acid, crotonicacid, itaconic acid, fumaric acid, maleic acid, monomethyl itaconate,monomethyl fumarate, monobutyl fumarate, maleic anhydride,2-acrylamido-2-methylpropane sulfonic acid, vinyl sulfonic acid, styrenesulfonic acid, 1-allyloxy-2-hydroxypropane sulfonic acid, alkyl allylsulfosuccinic acid, sulfoethyl (meth)acrylate, phosphoalkyl(meth)acrylates such as phosphoethyl (meth)acrylate, phosphopropyl(meth)acrylate, and phosphobutyl (meth)acrylate, phosphoalkylcrotonates, phosphoalkyl maleates, phosphoalkyl fumarates,phosphodialkyl (meth)acrylates, phosphodialkyl crotonates, and allylphosphate.

In some embodiments of the invention polymers formed by thepolymerization of ethylenically unsaturated monomers may containcopolymerized multi-ethylenically unsaturated monomers such as, forexample, allyl methacrylate, diallyl phthalate, 1,4-butylene glycoldimethacrylate, 1,2-ethylene glycol dimethacrylate, 1,6-hexanedioldiacrylate, and divinyl benzene.

In some embodiments of the invention it is desirable to incorporate intoone or more of the polymeric components functional monomers which impartspecialized performance to the aqueous dispersion. An example would bethe inclusion of monomers bearing functional groups which impartimproved adhesion to certain substrates. Ethylenically unsaturatedmonomers bearing such functional groups include but are not limited tofor example, vinyl acetoacetate, acetoacetoxyethyl(meth)acrylate,acetoacetoxypropyl(meth)acrylate, allyl acetoacetate,acetoacetoxybutyl(meth)acrylate,2,3-di(acetoacetoxy)propyl(meth)acrylate, vinyl acetoacetamide, andacetoacetoxyethyl(meth)acrylamide According to one embodiment, whenemulsion polymerization of one or more monomers is employed, chaintransfer agents such as, for example, halogen compounds such astetrabromomethane; allyl compounds; or mercaptans such as alkylthioglycolates, alkyl mercaptoalkanoates, and C₄-C₂₂ linear or branchedalkyl mercaptans may be used to lower the molecular weight of thepolymers formed by the polymerization of ethylenically unsaturatedmonomers and/or to provide a different molecular weight distributionthan would otherwise have been obtained with any free-radical-generatinginitiator(s). According to a separate embodiment when solutionpolymerization of one or more monomers is employed, organic solventsincluding but not limited alcohols such as isopropanol are used as chaintransfer agents to regulate molecular weight.

According to one embodiment, the oligomers having utility in accordancewith the invention have partial or no solubility in water. By this wemean that the dissolved concentration of oligomer dispersions in wateris no greater than 5 weight % at 25-50° C. at any pH between 2 and 12;preferably no greater than 2 weight %; and more preferably no greaterthan 0.1 weight %.

The aqueous dispersion, based on polymer solids, comprises: a) from 5 to99.9% by weight, based on the weight of solids in the aqueousdispersion, of one or more polymers having a number average molecularweight less than 10,000; b) from 0.1 to 95% by weight, based on theweight of solids in the aqueous dispersion, of one or more activeingredients selected from the group consisting of water soluble activeingredients, partially water soluble active ingredients, water insolubleactive ingredients and combinations thereof; and c) from 30% to 95% byweight of water.

Alternatively, a composition based on weight percent, is prepared inaccordance with the invention that comprises: (a) from 5 to 99.9% byweight, based on the weight of the composition, of one or more polymershaving a number average molecular weight less than 10,000; (b) from 0.1to 95% by weight, based on the weight of the composition, of one or moreactive ingredients selected from the group consisting of water solubleactive ingredients, partially water soluble active ingredients, waterinsoluble active ingredients and combinations thereof.

In some embodiments the inventive dispersions may be formed by blendingan aqueous dispersion comprising polymer dispersions and oligomerdispersions with an aqueous dispersion comprising other polymerdispersions. By blending is meant any means of combining or mixing atleast an aqueous dispersion comprising polymer dispersions and oligomerdispersions with an aqueous dispersion comprising other polymerdispersions. Means of blending may include adding a dispersioncomprising a polymer dispersion and an oligomer dispersion to an aqueousdispersion comprising another polymer dispersion or by adding adispersion comprising the latter polymer dispersion to a dispersioncomprising the former polymer dispersion and the oligomer dispersion.The dispersions may be combined in batch, semicontinuous, or continuousfashion.

According to one embodiment, aqueous low molecular weight polymerdispersions and oligomer dispersions are prepared by free radicalaqueous polymerization in the presence of a macromolecular organiccompound having a hydrophobic cavity, as disclosed in U.S. Pat. No.5,521,266. The macromolecular organic compound having a hydrophobiccavity useful in the method of the invention include cyclodextrin andcyclodextrin derivatives; cyclic oligosaccharides having a hydrophobiccavity such as cycloinulohexose, cycloinuloheptose, and cycloinuloctose;calyxarenes; and cavitands.

The cyclodextrin and cyclodextrin derivatives useful in the method ofthe invention are limited only by the solubility of the cyclodextrin andcyclodextrin derivative selected under the particular polymerizationconditions. Suitable cyclodextrins useful in the method of the presentinvention include, but are not limited to, a-cyclodextrin,b-cyclodextrin and g-cyclodextrin. Suitable cyclodextrin derivativesuseful in the method of the present invention include, but are notlimited to, the methyl, triacetyl hydroxypropyl and hydroxyethylderivatives of a-cyclodextrin, b-cyclodextrin and g-cyclodextrin. Thepreferred cyclodextrin derivative is methyl-b-cyclodextrin.

The cyclic oligosaccharides having a hydrophobic cavity, such ascycloinulohexose, cycloinuloheptose, useful in the method of theinvention are described by Takai et al., Journal of Organic Chemistry,1994, volume 59, number 11, pages 2967-2975.

The calixarenes useful in the method of the invention are described inU.S. Pat. No. 4,699,966, International Patent Publication WO 89/08092and Japanese patent publications 1988/197544 and 1989/007837.

The cavitands useful in the method of the invention are described inItalian patent application no. 22522 A/89 and Moran et al., Journal ofthe American Chemical Society, volume 184, 1982, pages 5826-5828.

The use of a macromolecular organic compound having a hydrophobic cavitywill be particularly useful when any of polymer and oligomer dispersionsare formed by aqueous free radical polymerization and when one or moreof the monomers and/or chain transfer agents used in the polymerizationhas a water solubility at 25-50° C. of no greater than 200millimoles/liter; no greater than 50 millimoles/liter.

When any of the polymer and oligomer dispersions are formed by aqueousfree radical polymerization and when one or more of the monomers and/orchain transfer agents used in the polymerization has a water solubilityat 25-50° C. of no greater than 200 millimoles/liter; no greater than 50millimoles/liter it may also be useful to introduce the monomers and/orchain transfer agents to the polymerization in the form of a monomeremulsion with an average droplet size of less than 50; less than 25microns.

The aqueous oligomer dispersion is combined with of one or more activeingredients selected from the group consisting of water soluble activeingredients, partially water soluble active ingredients, water insolubleactive ingredients and combinations thereof. According to someembodiments, active ingredients (AIs) are any compounds havingbiological activity. According to other embodiments, active ingredientsare compounds having pharmaceutical activity. According to otherembodiments, AIs are biologically active or pharmaceutically activecompounds that are applied to mammalian skin for a topical effect or tobe absorbed through the skin for a systemic effect. According to otherembodiments, AIs are compounds applied to a loci or an environment ofuse. According to other embodiments, AIs are compounds having aphysicochemical response when applied to a loci or an environment ofuse. According to other embodiments, AIs are compounds that protectsurfaces, including but not limited to for example, mammalian skin.

Active ingredients used in accordance to the present invention are watersoluble, partially water soluble, water insoluble and combinationsthereof. Water soluble, partially water soluble, water insoluble andmixtures thereof in the form of AIs that are liquids or solids and thatare amorphous, crystalline, semi-crystalline and combinations thereof.

According to one embodiment, the aqueous oligomer dispersion is combinedwith one or more water soluble AIs, wherein the AIs are amorphous,crystalline, semi-crystalline and combinations thereof. The watersoluble AIs are combined with the aqueous oligomer dispersion in anysuitable manner, including but not limited to for example, the one ormore AIs are present when one or more monomers are polymerized to formthe oligomer dispersion, the one or AIs are added to an oligomerdispersion, the oligomer dispersion as solids is dispersed in an aqueoussolution including one or more water soluble AIs. The water soluble AIsare either selectively partitioned within the oligomer dispersion or aredistributed in the oligomer (oil phase) and the aqueous phase.

According to separate embodiments, the aqueous oligomer dispersion iscombined with one or more partially water soluble or water insolubleAIs, wherein the AIs are amorphous, crystalline, semi-crystalline andcombinations thereof. The AIs are combined with the aqueous oligomerdispersion in any suitable manner, including but not limited to forexample, the one or more AIs are present when one or more monomers arepolymerized to form the oligomer dispersion, the one or more AIs areadded to an oligomer dispersion, the oligomer dispersion, including oneor more partially water soluble or water insoluble AIs partitionedtherein, is dispersed in an aqueous solution. The water soluble AIsmaybe selectively partitioned within the oligomer dispersion or may bedistributed in the oligomer (oil phase) and the aqueous phase. The AIsare either selectively partitioned within the oligomer dispersion or aredistributed in the oligomer (oil phase) and the aqueous phase.

According to one embodiment, the one or more active ingredients are anybiologically active agents, including agents having pharmacologicalactivity and immunological activity. The biologically active agentsexhibit morphologies selected from crystalline, semi-crystalline,amorphous and combinations thereof. Suitable biologically active agentsinclude but are not limited to for example, anti-inflammatory agents;anti-microbial agents; biocides; anti-bacterial agents, antiviral agentsincluding but not limited to Acylovir™ (water sol 37° C., 2.5 mg/mL),Lamivudine™ (water sol. 20° C., 70 mg/mL), Zidovudine™ (water sol. 25°C., 20.1 mg/mL), Zanamivir™ (water sol. 20° C., 18 mg/mL), Oseltamivir™(Tamiflu™), Ribavirin™, Pleconaril™ and Abacavir™ sulfate (water sol.25° C., 77 mg/mL), Amprenavir™ (water sol. 25° C. is 0.04 mg/mL),fosamprenavir™ (water sol. 25° C., 0.31 mg/mL), and valacyclovir™ (watersol. 25° C., 174 mg/mL), anti-retroviral agents, amino acids, peptides,proteins, DNA, RNA, lipids, lyposomes, adrenergic agents; adrenocorticalsteroids, adrenocortical suppressants, aldosterone antagonists, anabolicagents; analeptic agents; analgesic agents; anesthetic agents; anorecticagents; anti-acne agents; anti-adrenergic agents; anti-allergic agents;anti-amebic agents; anti-anemics; anti-angina agents; anti-arthriticagents; anti-asthmatics; anti-atherosclerotic agents; anticholinergics;anticoagulants; anticonvulsants; antidepressants; anti-diabetic agents;anti-diarrheals; anti-diuretics; anti-emetics; anti-epileptics;anti-fibrinolytics; anti-fungal agents; anti-hemorrhagics;anti-histamines; anti-hyperlipidemia agents; antihypertensives;anti-hypotensives; anti-infective agents; anti-migraines; anti-mitotics;anti-mycotics, anti-nauseants, anti-neoplastics, anti-neutropenics,anti-parasitics; antiproliferatives; antipsychotics; antirheumatics;antiseborrheics; antisecretories; antispasmodics; antithrombotisc;anti-ulcerative agents; appetite suppressants; blood glucose regulators;bone resorption inhibitors; bronchodilators, cardiovascular agents;cholinergics; depressants; diagnostic aids; diuretics; dopaminergicagents, estrogen receptor agonists; fibrinolytics; fluorescent agents;free oxygen radical scavengers; gastrointestinal motility effecters;glucocorticoids; hair growth stimulants; hemostatics; histamine H2receptor antagonists; hormones; hypocholesterolemics; hypoglycemics;hypolipidemics; hypotensives; imaging agents; immunizing agents;immunomodulators; immunoregulators; immunostimulants;immunosuppressants; keratolytics; LEIGH agonists; mood regulators;mucolytics; mydriatics; nasal decongestants; neuromuscular blockingagents; neuroprotectives; NMDA antagonists; non-hormonal sterolderivatives; plasminogen activators; platelet activating factorantagonists; platelet aggregation inhibitors; psychotropics; radioactiveagents; scabicides; sclerosing agents; sedatives; sedative-hypnotics;selective adenosine AI antagonists; serotonin antagonists; serotonininhibitors; serotonin receptor antagonists; steroids; thyroid hormones;thyroid inhibitors; thyromimetics; tranquilizers; amyotrophic lateralsclerosis agents; cerebral ischemia agents; Paget's disease agents;unstable angina agents; vasoconstrictors; vasodilators; wound healingagents; xanthine oxidase inhibitors; anti-cancer agents and combinationsof biologically active agents.

Suitable biologically active agents also include immunological agentssuch as allergens, pollens, and antigens from pathogens such as viruses,bacteria, fungi and parasites. The antigens may be in the form of wholeinactivated organisms, peptides, proteins, glycoproteins, carbohydratesor combinations thereof. Specific examples of pharmacological orimmunological agents that fall within the above-mentioned categories andthat have been approved for human use are known by those having skill inthe art.

According to other embodiments, the one or more active ingredients ofthe invention include but are not limited to any compound that exhibitsa chemical and/or physical effect. Suitable active ingredients of theinvention include, but are not limited to for example, gases,pesticides, herbicides, fragrances, anti-foulants, dyes, salts, oils,inks, cosmetics, catalysts, detergents, UV absorbers, organic compounds,and polymers, flavors, foods, photographic agents, biocides,pharmaceuticals, medicaments, and combinations thereof.

The aqueous oligomer dispersion, which includes one or more AIs iscombined with a second aqueous polymer dispersion. The resulting aqueousdispersion is a homogeneous dispersion or one that includes domains ofoligomer with AIs partitioned therein. According to one embodiment, theresulting aqueous dispersion comprises: (a) from 5 to 49.9% by weight,based on the weight of solids in the aqueous dispersion, of one or morepolymers having a number average molecular weight less than 10,000; (b)from 0.1 to 45% by weight, based on the weight of solids in the aqueousdispersion, of one or more active ingredients selected from the groupconsisting of water soluble active ingredients, partially water solubleactive ingredients, water insoluble active ingredients and combinationsthereof; and (c) from 94.9 to 5.1% by weight, based on the weight ofsolids in the aqueous dispersion, of one or more film forming polymershaving a number average molecular greater than 10,000; wherein the oneor more active ingredients (b) are partitioned in (a) prior to combiningwith (c) and water. When the aqueous dispersion dries and coalesces intoa useful article including but not limited to for example, a film, acoating, an adhesive, a pressure sensitive adhesive (PSA), a sealant, acosmetic, an ointment, a cream or a lotion, the one or more AI becomeincompatible within the article and diffuse out of the polymer to apolymer substrate interface which includes but is not limited anyconventionally known substrate and mammalian skin.

The monomers in both the oligomer dispersion and the polymer dispersionare adjusted according to the water solubility or the water insolubilityof the AIs. Water soluble AIs are partitioned into oligomers includingacid containing monomers. Partially soluble or water insoluble AIs arepartitioned into oligomers including non-ionic monomers.

The oligomer dispersion and the polymer dispersion are used to prepare adelivery system. According to one embodiment the system comprises alatex polymer blend. According to one embodiment, one component of theblend is a high molecular weight polymer having good film formingcharacteristics. The latex composition can be prepared into a suitablearticle such as a coating or PSA. A second component comprises anoligomer latex which includes one or more AIs partitioned therein. Theoligomer latex can also function as a reservoir of active ingredientsincluding water soluble and water insoluble pharmaceutical compositions.When the polymer latex dries into a film, the one or more AI s arereleased or delivered into a loci or environment of use or mammalianskin.

The aqueous dispersion of one more AIs is also dried by conventionaltechniques known in the art to provide a dry composition in the form ofarticles including but limited to form example, films, adhesives, PSAs,sealants, elastomers, and foams. According to some embodiments,compositions of the invention are prepared by drying the aqueous polymerdispersions, including, for example, spray drying, interfacialpolymerization, hot melt encapsulation, phase separation encapsulation,freeze drying, solvent evaporation, microencapsulation, solvent removalmicroencapsulation, coacervation, and low temperature microsphereformation and phase inversion.

The method of releasing the one or more AIs to an environment of use,loci or mammalian skin has utility as a delivery system in the form ofarticles not limited to for example a patch, an adhesive, a coating, asealant, a foam, an oil, and medical articles including but not limitedto for example, gauzes, devices, sutures, bandages, and adhesives.

Exemplary embodiments of the invention are summarized in the followingExamples. For examples 1-5, particle size was determined by opticalmicroscopy or using a Brookhaven Instruments Corp. 90Plus Particle SizeAnalyzer. Solids were determined by weight loss after 40 minutes at 150°C. Molecular weight distribution was determined by GPC analysis with aPolymer Labs Mixed C 300×7.5 mm column connected to an HP1100auto-sampler and pump equipped with a Polymer Labs evaporative lightscattering detector using polystyrene standards. Films prepared from theaqueous dispersions were characterized by electron microscopy, includingtransmission electron microscopy (TEM) and scanning probe microscopy(SPM, AFM).

Abbreviations Used in the Examples Ethoxylated C6 to C18 alkyl ethersulfate having from 1 to 40 Surfactant ethylene oxide groups permolecule (30% active in water) LA Lauryl acrylate BA Butyl acrylate MAAMethacrylic acid nDDM n-Dodecylmercaptan IPA Isopropyl alcohol OligomerLow molecular weight acrylic polymer having Mn <10,000. Me-β-CDMethyl-β-Cyclodextrin (BETA W7 M1.8), Wacker Chemicals (USA), Inc.,(50.8% active in water)

EXAMPLE 1 Low Molecular Weight Polymer Dispersions by EmulsionPolymerization

Emulsion polymerizations were carried out in a 5-liter round bottomflask with four necks equipped with a mechanical stirrer, temperaturecontrol device, condenser, monomer and initiator feed lines and anitrogen inlet.

Deionized water (1100 g), Methyl-β-cyclodextrin (59.2 g) and surfactant(18.8) were introduced into the reaction flask at room to form areaction mixture. The contents were heated to 85° C. while stirringunder nitrogen sweep. A monomer emulsion of deionized water (625 g),surfactant (14.1 g), monomers BA (1050 g, LA (450 g), nDDM (300 g) wasprepared separately.

At 85° C., 5.0 grams of ammonium persulfate in 25 grams of water wereadded to the reaction mixture. An acrylic dispersion (137.6 g at 45%solids) was added as a seed polymer. After the temperature stabilized at85° C., the monomer emulsion was fed into the reaction mixture over 100minutes together with an ammonium persulfate solution (1.0 gram in 100grams of water). At the end of the monomer emulsion feed, the reactionmixture was held at 85° C. for 20 minutes, cooled to 75° C., chased witht-butyl hydroperoxide and isoascorbic acid (0.51 g in 10 g of water and0.27 g in 25 g of water, respectively) in the presence of Fe₂SO₄ (4 g of0.15% solution). An addition chase was carried out at 60° C.

The acrylic dispersion (example 1A) has a total solids content of 54.1%and a particle size of 304 nm. The weight average molecular weight (Mw)and number average molecular weight (Mn) were measured at 2449 and 1842,respectively.

A second dispersion (example 1B) was prepared similar with BA (900 g),styrene (585 g), MAA (15 g) and nDDM (202.5 g). The particle size ofexample 1B was measured at 487 nm, solids at 38.3% and Mn at 1500.

EXAMPLE 2 Low Molecular Weight Polymer from Emulsion Polymerization

A low molecular weight polymer was isolated from the dispersion ofExample 1 upon evaporation of the water as a viscous oil. The oil wasfiltered through zeolite to obtain a clear oil, referred to as anacrylic oil (AO).

EXAMPLE 3 Low Molecular Weight Polymers from Solution Polymerization

Solution polymerizations were carried out in a 3-liter round bottomflask with four necks equipped with a mechanical stirrer, temperaturecontrol device, condenser, monomer and initiator feed lines and anitrogen inlet.

Isopropanol (600 g) was introduced into the reaction flask at roomtemperature. The content was heated to 82° C. under nitrogen sweep. Amonomer mixture was prepared containing BA (1800 g) and isopropanol (180g) was prepared separately. The monomer mixture was fed into thereaction flask over 120 minutes together with an initiator solutioncontaining Trigonox™ 125-C75 (72 g) in isopropanol (300 g). The reactionmixture was held at 85° C. for 30 minutes at the end of the feed and aninitiator solution containing Trigonox™ 125-C75 (18 g) in isopropanol(168 g) was added. After 30 minutes at 85° C., another initiatorsolution containing Trigonox™ 125-C75 (18 g) in isopropanol (168 g) wasadded. The reaction mixture was held at 85° C. for 90 minutes and thencooled to room temperature.

The low molecular polymer was isolated by the stripping of theisopropanol using a rotary evaporator to yield clear viscous oil. The Mwand Mn of the polymer were measured by GPC at 5556 and 4190,respectively.

EXAMPLE 4 Low Molecular Weight Polymer Dispersion by SolutionPolymerization

A stable aqueous dispersion was prepared that included 4 g of lowmolecular weight polymer (Example 3, 100 BA/1.9 iPrOH, Mn 4191), 0.4 gof Neodol 45-7, 0.5 g of RM8W (17.5% solid) and 5.1 g of water. Themixture is sonicated for 1 minute to yield dispersion with a particlesize of 0.5-1 and total solids of ˜40%.

EXAMPLE 5 Aqueous Dispersions of Low Molecular Weight Polymer andPartially Water Soluble Active Ingredients

Aqueous dispersion of Example 1A (10 g) was mixed with methyl salicylate(19 g) under ambient conditions. The aqueous dispersion was viewed underan optical microscope. The particles visibly swelled to from 0.8-1microns within 30 minutes. The theoretical particle size withquantitative swelling is 830 nm.

Alternatively, a dispersion derived from solution polymerization(example 4) is to prepare the dispersion in a similar manner.

EXAMPLE 6 Aqueous Dispersion of Low Molecular Weight Polymer and WaterInsoluble Active Ingredient

Ibuprofen™ (2.5 g) was dissolved in low acrylic oil (5 g, Example 1A) at40° C. The oil mixture solution was added to an aqueous solutionconsisting of water (6 g), Tergital™ 15-S-5 (0.5 g) and sodium laurylsulfate SLS (1 g) at 60° C. The aqueous mixture was sonicated for 1minute (40% power setting of a maximum 500 W Sonicator Processor, XL) at60° C. to yield an aqueous dispersion of acrylic oil/Ibuprofen in waterwith particle sizes ˜200 nm. The aqueous dispersion as prepared included16.7% by weight Ibuprofen™ and 33.3% acrylic oil by weight in water. Thedispersion was stable at room temperature for 30 minutes after whichcrystal formation in the form of needles can be seen under an opticalmicroscope.

Alternatively, a low molecular weight polymer derived from solutionpolymerization (Example 3) is combined with Ibuprofen™ in a similarmanner to form an aqueous dispersion.

EXAMPLE 7 Aqueous Dispersion of Low Molecular Weight Polymer, WaterInsoluble Active Ingredient and Film Forming Polymers

Aqueous dispersion from Example 4 (6 g) was mixed with a film formingadhesive dispersion, Robond™ PS-90 (14 g) to form an aqueous dispersionconsist of 5.4% Ibuprofen™, 10.8% acrylic oil and 34.7% of highmolecular weight polymer by weight in water. The aqueous dispersion wasstable for over a week without crystal formation as viewed under anoptical microscope.

EXAMPLE 8 A Composition of Active Ingredient in Polymer

An aliquot (8 g) of the aqueous dispersion in example 5 was added to an8 inches diameter Teflon™ petri dish and dried under ambient conditions.The final dry composition consists of 70% high molecular weight polymer,10% Ibuprofen™ and 20% acrylic oil. Ibuprofen™ was observed in thepolymer phase as domains (˜125 nm) as observed by Transmission ElectronMicroscope with sample microtoned under cryogenic conditions and stainedwith RuO₄.

1. An aqueous dispersion comprising: a) from 5 to 99.9% by weight, basedon the weight of solids in the aqueous dispersion, of one or morepolymers having a number average molecular weight less than 10,000; b)from 0.1 to 95% by weight, based on the weight of solids in the aqueousdispersion, of one or more active ingredients selected from the groupconsisting of water soluble active ingredients, partially water solubleactive ingredients, water insoluble active ingredients and combinationsthereof; and c) from 30% to 95% by weight of water.
 2. An aqueousdispersion comprising: (a) from 5 to 49.9% by weight, based on theweight of solids in the aqueous dispersion, of one or more polymershaving a number average molecular weight less than 10,000; (b) from 0.1to 45% by weight, based on the weight of solids in the aqueousdispersion, of one or more active ingredients selected from the groupconsisting of water soluble active ingredients, partially water solubleactive ingredients, water insoluble active ingredients and combinationsthereof; and (c) from 94.9 to 5.1% by weight, based on the weight ofsolids in the aqueous dispersion, of one or more film forming polymershaving a number average molecular greater than 10,000; wherein the oneor more active ingredients are partitioned in (a) prior to combining thecomponents and water.
 3. A composition comprising: (a) from 5 to 49.9%by weight, based on the weight of the composition, of one or morepolymers having a number average molecular weight less than 10,000; (b)from 0.1 to 45% by weight, based on the weight of the composition, ofone or more active ingredients selected from the group consisting ofwater soluble active ingredients, partially water soluble activeingredients, water insoluble active ingredients and combinationsthereof; and (c) from 94.9 to 5.1% by weight, based on the weight of thecomposition, of one or more film forming polymers having a numberaverage molecular greater than 10,000; wherein the one or more activeingredients are partitioned in (a) prior to combining the components. 4.A film prepared from the aqueous dispersion of claim
 2. 5. An adhesiveprepared from the aqueous dispersion of claim
 2. 6. A method forstabilizing one or more active ingredients comprising the steps of: a)preparing an aqueous dispersion comprising from 5 to 99.9% by weight,based on the weight of solids in the aqueous dispersion, of one or morepolymers having a number average molecular weight less than 10,000; andb) combining the aqueous dispersion with from 0.1 to 95% by weight,based on the weight of solids in the aqueous dispersion, of one or moreactive ingredients selected from the group consisting of water solubleactive ingredients, partially water soluble active ingredients, waterinsoluble active ingredients and combinations thereof.
 7. A method forreleasing one or more active ingredients from an aqueous dispersioncomprising: a) preparing a first aqueous dispersion comprising from 5 to49.9% by weight, based on the weight of solids in the aqueousdispersion, of one or more polymers having a number average molecularweight less than 10,000; b) combining the aqueous dispersion with from0.1 to 45% by weight, based on the weight of solids in the aqueousdispersion, of one or more active ingredients selected from the groupconsisting of water soluble active ingredients, partially water solubleactive ingredients, water insoluble active ingredients and combinationsthereof; and c) combining the first aqueous dispersion with a secondaqueous dispersion from 94.9 to 5.1% by weight, based on the weight ofthe composition, of one or more film forming polymers having a numberaverage molecular greater than 10,000; wherein the one or more activeingredients are partitioned in the first aqueous dispersion prior tocombining with the second aqueous dispersion; and d) drying the mixtureof aqueous dispersions to form a film or a coating.
 8. The methodaccording to claim 7 wherein a film is formed after drying thecombination of the aqueous dispersions.